CN104105487A - Oromucosal liquid estradiol compositions - Google Patents

Oromucosal liquid estradiol compositions Download PDF

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CN104105487A
CN104105487A CN201380004808.0A CN201380004808A CN104105487A CN 104105487 A CN104105487 A CN 104105487A CN 201380004808 A CN201380004808 A CN 201380004808A CN 104105487 A CN104105487 A CN 104105487A
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estradiol
solution
administration
dosage
ester
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弗朗西斯科威廉姆斯亨利库斯玛丽亚·马库斯
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INNOTESTO bvba
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
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  • Endocrinology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention relates to low dose estradiol solutions for oromucosal administration suitable in replacement therapy or suppletion of low estradiol levels and also for preventing, alleviating or treating symptoms associated with low endogenous levels of estradiol in female subjects.

Description

The estradiol compositions of oral mucosa liquid
Technical field
The present invention relates to low dose of estradiol solution, it is for being adapted at the oral mucosa administration supplementing of alternative medicine or low estradiol level, and for the symptom of preventing, alleviating or treatment is relevant to the low level of estradiol of female patient.
Technical background
That current estradiol therapy comprises is oral, percutaneous, injection and vagina preparation.Percutaneous transmits and comprises patch, gel, lotion and spraying, and vagina product comprises suppository, cream and ring.
Estradiol, during as tablet, pill or capsule oral, in gastrointestinal absorption and in liver after metabolism (first pass metabolism), major part changes into estrone.This causes the unbalance of estradiol/estrone ratio, and this ratio is generally 1:1 in premenstrual women.This unbalance variation that mainly can cause lipid and thrombin.Parenteral product (percutaneous, vagina) has been avoided this liver first pass metabolism, and is therefore considered to the first-selection of estradiol suppletion.
Conventionally, it may be wise using the hormone estradiol of lowest dose level, because overdose may cause the side effect relevant to non-physiologic hormonal readiness.The parenteral product of low dosage is first-selected, because the low dosage of (1) administration, the physiological ratio between (2) estradiol and metabolite estrone level thereof, and the detrimental effect risk of (3) so reduction.Because endometrium does not very have hypertrophy during the estradiol of low dosage in administration, therefore, when relative treatment (continuously or circulation co-administered progestogen) is not absolute needs, it can be also useful using low-down dosage.
In the research of the estradiol product to new, considered parenteral administration, comprise the product for nose and oral mucosa administration.US5955098 discloses cheek aerosol spray, and it comprises propellant 50-95%, non-polar solven 5-50%, active pharmaceutical compounds 0.001-15% (comprising estradiol) and flavoring agent 0.05-5%.US6110486 discloses and has contained the cheek spraying that is dissolved in the estradiol in acceptable polar solvent on materia medica, and in the % by weight of compositions, it comprises polar solvent 75-99.8%, reactive compound 0.68-40%.As the solvent for spraying, used low-molecular-weight alcohols and the polyalcohols of 200-1000MW (preferably 200-600), and also had low-molecular-weight alcohols and polyalcohols, as G & W.Illustrational is the spray agent that contains estradiol and 85% Polyethylene Glycol.Yet this solvent has bitter smell of scorching in mouth, mainly the composition based on such forms spraying, for life-time service, acceptable poor.
US2011/0097405 discloses a kind of oral mucosa estradiol product, and it is mainly to absorb in oral cavity, rather than in gastrointestinal tract.It is water-solubility membrane, is called Oryza glutinosa charta (wafer).The Oryza glutinosa charta fast quick-dissolving agent in mouth that contains like this low dose of estradiol, discharges estradiol thus, and it can be absorbed by oral mucosa approach subsequently.The cheek sheet that comprises estradiol is disclosed in EP0371466 and WO2010/089078.The medicated paper that contains estradiol and cyclodextrin for oral mucosa administration is disclosed in EP1867321.
The preparation of 17 beta estradiols of the aqueous solution of using for nose and/or the DM-β-CD complex of progesterone has been described in EP0349091.A kind of such preparation that contains 17 beta estradiols compound in methyl-β-cyclodextrin has allowed with trade name Aerodiol tMfor medical.This nose spray product, with the low dosage administration of 300 μ g/ days, equally effective with 2mg oral tablet/sky in treatment menopausal symptom.It demonstrates the side effect of reduction, that is, less mazalgia outbreak and drug withdrawal are hemorrhage.In addition, reported to some lipid parameter the beneficial effect to the mark of bone resorption, bone formation and bone mineral density.Finally, found to compare with oral medication, used intranasal administration estradiol, tenderness of breasts sense is lower.
Due to the side effect of frequent nasal administration, recommend Aerodiol tMbe administered once every day with high dose, causes high peak estradiol level.In 10-30min, reach these levels, and after administration in approximately two hours level fall 10% (Devissaguet etc., the Eur.J.Drug Metabol.Pharmacokinetics1999 to peak value after rise; 24:265-271).This means Aerodiol of intranasal administration every day tMcausing " (pulsatile) of beating " spectrum, comprise large peak every day, is then that wherein estradiol level remains on the low-level stage.By the Aerodiol of aequum tMpeak level after nose spray delivery 300 μ g estradiol reaches the value of 1400pg/l.The normal estradiol level of each chemical examination is slightly different, but scope is 100-500pg/ml in menstrual cycle process.This means and use nose Aerodiol tMthe peak level of the 1400pg/ml obtaining is than high approximately 3 times of the highest normal level of Pre-menopausal Women.
Another defect relevant to nasal administration be as cause in the flu or irritated situation of watery nasal discharge or nasal obstruction, approaching nasal mucosa will be hindered.This causes inconsistent snuffing to be received, or does not even have snuffing to receive.Aerodiol tMproduct feature instructed in this case, patient can pass through the Aerodiol of oral mucosa administration doubling dosage tM, to reach similar estradiol serum levels.
In addition, nasal administration can produce local side effects in nose, as local excitation, itch, watery nasal discharge (rhinorrhoea) sneeze and epistaxis.Repeatedly nasal administration has increased these undesirable side effect.
First object of the present invention is to avoid nasal administration and the relative side effect of estradiol.
Second object of the present invention is to provide the estradiol compositions for oral mucosa administration, and it does not need the estradiol of administration high dose, as for example, and oral mucosa administration Aerodiol tMthe doubling dosage needing.
In addition, the object of this invention is to provide the new dosage for estradiol administration, it provides the physiology's pharmacokinetics spectrum that reaches normal estradiol blood plasma level.A special object has been to provide the dosage with low estradiol peak level, particularly high estradiol level is remained on to the scheme below 500pg/ml, and the peak serum levels of having avoided the existing nasal preparation of administration to see.
A further object of the invention is to provide the new and improved dosage form that comprises low dose of estradiol preparation, be used for being applicable to oral mucosa, its (1) has transmitted similar to nasal administration or better bioavailability, (2) providing thus can be by the dosage form of dosage personalization, and (3) have medicine frequency flexibly and given better patient's compliance with (4).
Summary of the invention
In one aspect, the present invention relates to the solution of a kind of non-aqueous (or being non-aqueous substantially), the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, the C of 5-30% (v/v) 2-C 5the C of alcohol and 70-95% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid, is used for the treatment of the mankind women of the estradiol level with reduction by the described solution of oral mucosa administration doses, described dosage contains 0.01-0.3mg estradiol, or acceptable hydrate or ester on its materia medica of equivalent.
In one aspect of the method, the present invention relates to a kind of solution, the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, the C of 5-30% (v/v) 2-C 5the C of alcohol and 70-95% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid, described solution is for the manufacture of medicine, described medicine is used for the treatment of the mankind women of the estradiol level with reduction by the described solution of oral mucosa administration doses, described dosage contains 0.01-0.3mg estradiol, or acceptable hydrate or ester on its materia medica of equivalent.
Solution of the present invention can carry out administration with predetermined content by various administrations, and in a time point or a plurality of time point administration, the administration of selection makes resulting estradiol blood serum level approach normal level all day in administration.Suitably, solution of the present invention can carry out administration women's estradiol serum levels is returned to the mode of normal level.
According to these aspects of the present invention, therefore can be as described below, by single or multiple administration, carry out dosage described in administration.Described dosage can have the described solution of 10 μ l to 300 μ l volumes, preferably 25 μ l to 100 μ l-for example, 25 μ l, 50 μ l or 100 μ l.
Can with the described solution of doses, treat mankind women at one or more time points.Solution of the present invention can be administered once every day or every day repeatedly, for example, every day twice, three times, four times, five times or six dosage.In some embodiments, multiple dosing can carry out with the time period of rule, for example, per hour or every two hours, three hours or four hours.
In one embodiment, can be in the time period in 1 to 4 hour scope dosage off and on, particularly with the interval equating, carry out administration, for example, with approximately 1, or 2, or the interval of 3 or 4 hours.
Conventionally, every day can an administration 1-6 dosage, for example, every day 1,2,3,4,5 or 6 dosage, or every day 1-4 dosage, or every day 1-2 dosage.
In aspect different, the present invention relates to a kind of mankind women's the method that treatment has the estradiol level of reduction, described method is included in one or more time points and by oral mucosa, the solution of doses is delivered medicine to the mankind's female patients needing, the estradiol that described solution contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, the C of 5-30% (v/v) 2-C 5the C of alcohol and 70-95% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid; Wherein by single or multiple administration, give described dosage, and described dosage comprises 0.01-0.3mg estradiol, or acceptable hydrate or ester on its materia medica of equivalent.
Described dosage can have the described solution of 10 μ l to 300 μ l volumes, preferably 25 μ l to 100 μ l-for example, 25 μ l, 50 μ l or 100 μ l.
Can carry out oral mucosa administration by the device of spraying, make up a prescription pen or transmission drop.Therefore, further in, the invention provides comprise spraying, the pen and transmit the dosage form of the device of drop of making up a prescription, described dosage form comprises herein the specially solution of explanation.
Estradiol solution of the present invention can be in the dosage of adjusting separately by following one or more modes, described mode is: 1. by dosage itself, 2. spraying or the volume of drop, 3. spraying or the quantity of drop, 4. by single or multiple administration, 5. one or more time points, and 6. by the frequency of administration every day.Can carry out solution described in administration according to such scheme.
In one embodiment, solution of the present invention or contain 10-30% ethanol (v/v), 70-90% isopropyl myristate or isopropyl palmitate and 0.01-0.9% estradiol for the present invention's solution, or acceptable hydrate or ester on its materia medica of equivalent.
In one embodiment, solution of the present invention or contain 0.01-0.5% (w/v) estradiol for the present invention's solution, or acceptable hydrate or ester on its materia medica of equivalent.
In again aspect another, the present invention relates to comprise the solution of acceptable hydrate on its materia medica of estradiol as described in detail or equivalent or ester herein, be used for the treatment of, prevent or alleviate the symptom being caused by not enough endogenous estrogen growing amount in mankind women, or for the manufacture for the treatment of, preventing or alleviate in the medicine of the symptom being caused by not enough endogenous estrogen growing amount in mankind women.The example of these symptoms comprises headache, feels sick, vasomotor symptoms (upsurge), the symptom of urogenital atrophy be, the risk of bone fracture of the reduction of bone mineral density, osteoporosis and raising or incidence rate.
In again aspect another, the present invention relates to a kind for the treatment of, prevent or alleviate the method for the symptom being caused by not enough endogenous estrogen growing amount in mankind women, described method comprises the solution of acceptable hydrate on its materia medica that oral mucosa administration comprises estradiol as described in detail or equivalent herein or ester.The example of these symptoms as mentioned above.
Of the present invention again aspect another in, the solution of the estradiol as described in detail is herein provided, by single or multiple administration, oral mucosa approach via the described solution of predetermined content, by the administration at one or more time points, be used for the treatment of the estradiol level reducing in mankind women, or for the manufacture of the medicine for the treatment of the estradiol level reducing in mankind women, described predetermined content represents the dosage of 0.01-0.3mg estradiol, in the volume of 10 μ l to 300 μ l scopes, preferred 25 μ l to 100 μ l; For example 25 μ l, 50 μ l or 100 μ l.Had been found that estradiol administration by this way causes the controlled raising to the proportional estradiol serum levels of estradiol content of administration.
Of the present invention again aspect another in, the solution of a kind of non-aqueous (or being non-aqueous substantially) is provided, the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, the C of 5-30% (v/v) 2-C 5the C of alcohol and 70-95% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid, is used for the treatment of the mankind women with upsurge; Wherein by solution described in oral mucosa administration, preferably by cheek, cheek upper jaw bone (buccomaxillary) or cheek gums (buccogingival) administration, upsurge is once administration occurs, dosage is 0.01-0.3mg estradiol, in the described solution of 10 μ l to 300 μ l scope volumes, preferred 25 μ l to 100 μ l; For example 25 μ l, 50 μ l or 100 μ l.
Of the present invention again aspect another in, the solution of estradiol a kind of as that describe in detail is herein provided, by single or multiple administration, oral mucosa approach via the described solution of predetermined content, by the administration at one or more time points, be used for the treatment of the estradiol level that reduces in mankind women after menopause or for the manufacture of the medicine of the estradiol level reducing in mankind women after treatment menopause; Described predetermined content represents the dosage of 0.01-0.3mg estradiol, in the required time period, women's estradiol level is raise and/or is remained on higher than 20 thus, higher than 30, higher than 40 or higher than 50pg/ml, and lower than 500pg/ml, especially between 50-500pg/ml.
In again aspect another, the present invention relates to the solution of a kind of non-aqueous (or being non-aqueous substantially), the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, the C of 5-30% (v/v) 2-C 5the C of alcohol and 70-95% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid.
In some embodiments, C 2-C 5can be ethanol, and C 2-C 6alcohol and C 8-C 22the ester of fatty acid can be isopropyl myristate or isopropyl palmitate.
The specific embodiment
Any list of references of quoting is herein incorporated herein by reference.
As used in this article, " patient refers to the mankind to term.Term " patient " and " patient " can exchange use.
Term " level ", " serum levels ", " blood level ", " blood plasma level " and " blood serum level " can exchange use in this article.
As used in this article, term " oral mucosa " refers to cheek, cheek upper jaw bone, Sublingual, gums, cheek gums and palate.
Term " solution " refers under ambient temperature and body temperature it is the solution of liquid.
While using in this article, term " estradiol " represents 17-alpha-estradiol or 17-β-estradiol.Preferred estradiol is the form of 17-β-estradiol in the present invention.Term " estradiol " and " derivatives of estradiol " are used for containing acceptable hydrate, ester or derivant on estradiol self and any materia medica thereof.Term " acceptable ester on the materia medica of estradiol " refers to the ester of estradiol, as, for example, estradiol valerate, estradiol acetate, estradiol phenylpropionic acid ester, estradiol propionic ester, estradiol heptanoate, estradiol undecylate, estradiol benzoate, Estradiol Cypionate, estradiol sulfuric ester and E2V J1242.
Term " C 2-C 5alcohol " refer to there are two to the alcohols of five carbon atoms, for example, 2,3,4 or 5 carbon atoms.These specific subgroup is side chain or the non-side chain C that monohydroxy is saturated 2-C 5alcohols, as for example ethanol, 1-propanol, isopropyl alcohol, butanols, amylalcohol, or dihydroxy alcohols, as propylene glycol, or trihydroxy alcohols, as glycerol.
Phrase " C 8-C 22fatty acid and C 2-C 6acceptable ester on the materia medica of alcohol " refer to such ester and comprise vegetable oil.C 8-C 22fatty acid comprises the fatty acid (for example, 8,10,12,14,18,20 or 22 carbon atoms) with 8 to 22 carbon atoms, as, for example, myristic acid, Palmic acid, stearic acid, arachidic acid or oleic acid.C 2-C 6alcohol comprises the alcohols (for example, 2,3,4,5 or 6 carbon atoms) with 2 to 6 carbon atoms, particularly as the C describing in detail herein 2-C 5alcohol, and the homologue with 6 carbon atoms, as hexanol, also comprise glycols and three alcohols, as ethanol, isopropyl alcohol, propylene glycol and glycerol.
C 8-C 22fatty acid and C 2-C 6the example of the ester of alcohol comprises isopropyl myristate, isopropyl palmitate and isopropyl stearate.The example of vegetable oil is Oleum sesami, Semen Maydis oil, Oleum Ricini and olive oil.
Term " non-aqueous (or the substantially non-aqueous) " meaning is not moisture or only containing the solution of a small amount of water as used in this article, as lower than 5%, or lower than 3%, or lower than 1% water.
Term " v/v " refers to the ratio of volume and volume, and " w/v " refers to the ratio of weight and volume.
While relating to numerical value use, term " about " has the meaning that association area is understood conventionally.In specific embodiment, term " about " can not considered, maybe can be interpreted as representing numerical value ± 10%; Or ± 5%; Or ± 2%; Or ± 1%.
By oral mucosa administration solution of the present invention.This expression delivers medicine to oral cavity by the solution of given dose or volume, and active drug substance is absorbed via one or more oral mucosa (tongue, Sublingual, cheek, gums and palate) subsequently.
Solution of the present invention can pass through patient oneself administration easily, or carrys out administration by doctor, care-giver or nurse.
Can carry out solution described in administration with single or multiple administration, represent once all or come with one or more sub-doses the estradiol of administration given dose.For example, the spray solution of the ejection that can be administered once, represents all required dosage, maybe can be administered once, twice or the smaller dose of ejection repeatedly, and the preferred apart short period.
In particular of the present invention, described solution contains 0.01-0.9% (w/v), or 0.05-0.8% (w/v), or 0.1-0.7 (w/v) or 0.2-0.6% (w/v) or 0.3-0.5% (w/v), or 0.1-0.4% (w/v), or the estradiol of 0.1-0.3% (w/v), or acceptable hydrate or ester on its materia medica of equivalent.
After measuring estradiol serum-concentration, conventionally can determine the content of the estradiol of administration.According to the result of these measurements, doctor can determine to output lower or higher concentration estradiol solution prescription and/or can by dosage itself or administration volume or administration number of times or every day administration frequency adjust separately dosage regimen.
In particular of the present invention, described solution contains 5-30% (v/v), or 10-30% (v/v), or 5-25% (v/v), or 10-25% (v/v), or the C of 15-25% (v/v) 2-C 5alcohol, preferred alcohol.
In the solution that contains ethanol of the present invention, while existing with the concentration of at least 10% (v/v), ethanol is not only as solvent, but also as effective anti-microbial preservative.This is favourable, because this makes no longer to need to use and comprise in such solution other antiseptic.
In one embodiment, described solution contains 5-40% (v/v), or the C of 5-35% (v/v) 2-C 5alcohol.The solution containing over 30% (v/v) concentration of alcohol may cause stimulation or other side effect, but these can assign to alleviate by adding specific one-tenth.
In particular of the present invention, the C that described solution contains 70-95% (v/v) 2-6alcohol and C 8-22the ester of fatty acid, or 75-90% or the such ester of 80-8%.
As mentioned above, solution of the present invention can carry out administration with predetermined content by various administrations, and in a time point or a plurality of time point administration, the administration of selection makes resulting estradiol blood serum level approach normal level all day in administration.Therefore, can carry out administration solution of the present invention with predetermined content and by various administrations, in a time point or a plurality of time point administration, so that estradiol serum levels is increased to normal value, particularly be increased to the level higher than 20pg/ml, or in the scope of serum levels in 10-500pg/ml, 50-100pg/ml or 100-500pg/ml.In one embodiment, described serum levels maintains and surpasses 3 hours, preferably under the level higher than 20pg/ml, maintains 3 hours.
Solution of the present invention can be administered once every day or administration every day repeatedly, for example, every day twice, three times, four times, five times or six times.Especially, can carry out multiple dosing with the time period of rule, for example, per hour or every two hours, three hours or four hours.
In one embodiment, can be at dosage, the particularly interval to equate described in the discontinuous ground administration of the time period of 1 to 4 hour scope, for example, with approximately 1, or 2, or 3, or the interval of 4 hours.
Described solution can carry out administration by 1-6 administration every day, for example, every day, 1,2,3,4,5 or 6 administration, or by administration every day 1-4 time, or by 1-2 administration every day.
Solution of the present invention administration in every way, for example, by spraying or as drop.Operable device is (aseptic or non-sterile) multiple dose or single dose solution, or the spraying of multiple dose or single dose or drop device, or anyly can the designated volume such as 25 μ l, 50 μ l etc. be transferred to from it to other containers or the pen in oral cavity.Device for administration estradiol solution of the present invention comprises the vial with sprayer unit, and any for administration 25 μ l to 120 μ l scopes, for example, other devices of 25 μ l, 50 μ l, 70 μ l, 90 μ l, 100 μ l or 120 μ l volumes (using or do not use propellant).While using spraying, can use about 25-200 μ l/ agent (or injection) scope that has known in the art, for example, the device of any kind of approximately 50,75,100,125,150,175 μ l capacity.In addition, drop dispenser or fountain-pen dosimeter are also applicable to solution to deliver medicine to patient's oral cavity.
In specific embodiment, the estradiol that for example the every dose volume of solution of the present invention by drop, fountain-pen dosimeter or spray delivery comprises 10-300 μ g estradiol scope dosage, as 25-300 μ g estradiol, for example, 50-300 μ estradiol.Conventionally, the dosage of every dose comprises 10-200 μ g estradiol, as 10-100 μ g estradiol, or 25-100 μ g estradiol.As daily dose, estradiol that can administration 100-600 μ g total amount, the preferably estradiol of 100-300 μ g.
The invention still further relates to as the purposes in the estradiol level that specially the estradiol solution of explanation reduces in treatment women herein, by the described solution of oral mucosa administration predetermined content, cause the controlled raising to the proportional estradiol blood serum of the estradiol content level of administration.
For every 0.05mg estradiol of administration, the controlled raising of estradiol serum levels can be between about 150-300pg/ml, or for every 0.025mg estradiol of administration, between about 75-150pg/ml.
Use the dosage regimen of estradiol solution of the present invention can avoid heavy dose of administration, cause thus the peak level of estradiol, exceed normal level a lot.Dosage regimen of the present invention has been avoided the local side effects relevant to frequent nasal administration, as local excitation, pruritus, watery nasal discharge, sneeze and epistaxis.In addition, use solution of the present invention, with the aqueous cyclodextrin formulations, particularly Aerodiol of estradiol tMpreparation is compared, can the lower dosage of administration.
Dosage for estradiol administration of the present invention provides the physiology's pharmacokinetics spectrum close to normal estradiol blood plasma level.In addition, dosage of the present invention demonstrates lower estradiol peak level, the highest estradiol level is remained on lower than 500pg/ml simultaneously, and the peak serum levels of having avoided administration nasal preparation to see.
Estradiol dosage of the present invention (1) transmits or better bioavailability similar to nasal administration, (2) providing thus can be by the dosage form of dosage personalization, and (3) have medicine frequency flexibly and given better patient's compliance with (4).
In another embodiment, solution of the present invention comprises more active drug substance, as progesterone or another kind of progestogenic compounds, for example, in the scope of 0.1-5% (w/v), 0.5-4% (w/v), 1-3% (w/v/) or 1.5-2.5% (w/v).
In some embodiments, the solvent in solution of the present invention can by or substantially by the C of 5-30% (v/v) 2-C 5the C of alcohol and 70-90% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid forms.In other embodiments, solution of the present invention can by or substantially by the C of the 5-30% (v/v) of acceptable hydrate or ester, 5-30% (v/v) on the estradiol of 0.01-0.9% (w/v) or its materia medica of equivalent 2-C 5the C of alcohol and 70-90% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid forms.
In addition, solution of the present invention can also comprise sweeting agent or flavoring agent, for example, and with the concentration of 1-5% (w/v).The example of sweeting agent or flavoring agent can find in materia medica document.For example, glucide can be added in solution.Any composition to be added preferably in the list of the chemical substance GRAS list for pharmaceutical preparation (being commonly referred to be safe), and is to be allowed at present those in local and parenteral formulation.
In other embodiments, solution of the present invention can also contain antioxidant, viscosity intensifier, viscosity modifier, surfactant and excipient, and regulation and control solution adheres to the mucosa in oral cavity.All that excipient can be known (for example, Remington:The Science and Practice of Pharmacy, the 21st edition, PA Lippincott Williams & Wilkins, 2005) from materia medica document.
In the situation that solution is suitable for transmitting with Sprayable therein, can add propellant.Suitable propellant comprises containing HCFC, containing hydrofluorocarbon, as HFA-227ea, dimethyl fluoro-propane, tetrafluoropropane, butane, iso-butane, dimethyl ether, diethyl ether and any other non-CFC and CFC propellant.Preferred propellant is HFA 134a (HFA134a).
The present invention relates to be used for the treatment of the estradiol solution of the estradiol level that female patient reduces, by the described solution via oral mucosa administration predetermined content, by single or multiple administration, in one or more time point administrations, described content represents the dosage of 0.01-0.3mg estradiol, causes thus the raising to the proportional estradiol serum levels of estradiol content of administration.
In one aspect of the method, the present invention relates to the estradiol solution describing in detail as herein, be used for the treatment of, alleviate, alleviate or prevent in female patient by lacking the health that (not enough) endogenous estradiol blood level causes, as headache, feel sick, risk of bone fracture or the incidence rate of depression, vasomotor symptoms (upsurge), the symptom of urogenital atrophy, the reduction that loses libido, bone mineral density, osteoporosis or raising.
In a preferred embodiment of the invention, female patient to be treated is the women with deficiency (too low) estradiol level, and this is common after menopause and menopause.In the women of childbearing age, in the different time sections of menstrual cycle, normal estradiol level scope is 100-500pg/ml.At perimenopause, estradiol level, lower than 100pg/ml, at postmenopause, is down to 10-20pg/ml.Value scope lower than the normal estradiol level of 100pg/ml is relevant to upsurge, and can send the signal of menopause.Menopause is the end of menstruation, and it is caused by the estrogen production reducing.In menopause process, the quantity of follicle falls to lower than specific threshold value, and ovary no longer produces mature follicle and gonadal hormone.As a result of, along with menopause, finish fertility.The mean age that women experiences menopause is 45-50 year.Because life expectancy becomes more and more longer, can expect now that the most life of women will spend in the postclimacteric stage.
In the further embodiment of the present invention, using according to the female patient of estradiol Solution In The Treatment of the present invention is the women who hysterectomizes.The total hysterectomy inside fascia of removing both sides ovary is postoperative, and the hormone of estrogen (estradiol) and progestogen (progesterone) produces and stops completely.
In thering is complete endometrial women, use estradiol monotherapy to stimulate endometrial hypertrophy.The relativity that simultaneously realizes progesterone is also important, and it has stopped endometrial hypertrophy, and this is non-existent in postmenopausal women.Because endometrial hypertrophy is the aborning risk factor of carcinoma of endometrium, should pass through co-administered progesterone, continuously or with circulation therapeutic regimen, protect the women's who just experiences estradiol monotherapy endometrium.
Therefore it is favourable, in postmenopausal women, in conjunction with estradiol solution of the present invention, using the progesterone solution for oral mucosa co-administered.Such progesterone solution is the solution for containing 0.1-5% (w/v) progesterone in solvent for example, the C that described solvent comprises 10-30% (v/v) 2-C 5the C of alcohol and 70-90% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid, for example, the solution of ethanol and isopropyl myristate.In specific embodiment, described solution contains 0.5-4% (w/v), or 1-3% (w/v) progesterone.
Think that the serum progesterone level of 5 to 30ng/ml (15-90nmol/L) is representational luteal phase of progesterone level, but also found in the literature the level of 2-20ng/ml (6-60nmol/L).Knownly in the controversies in hormone replacement in the elderly of postmenopausal women, do not need specific level that the protection of suitable endometrium is provided, but expection is approximately 2ng/ml and Geng Gao.
Further, the invention provides the preparation of solution form as described herein, the non-aqueous solution that it comprises 0.1-5% concentration progesterone, for oral mucosa administration.By the described solution of administration predetermined content, by single or multiple administration, at one or more time points, described content represents the dosage of 0.1-3mg progesterone, can obtain the raising to the proportional progesterone serum levels of progesterone content of administration.The raising of progesterone serum levels can be approximately 0.3-2ng/ml/0.1mg progesterone (or about 1-6nmol/L/0.1mg progesterone).
Embodiment of the present invention relate to 1.5% (w/v) progesterone oral mucosa solution that for example comprises 150mg progesterone, 3.0ml ethanol and 7.0ml isopropyl myristate.The such solution of 100 μ l represents 1.5mg progesterone, and 50 μ l represent 0.75mg, and 25 μ l represent 0.375mg progesterone.
Other embodiments relate to and contain the liquid solution that is dissolved in the progesterone in solvent, and described solvent comprises ethanol and/or other C 2-C 5alcohol and isopropyl alcohol and/or other C 2-C 6alcohol and C 8-C 22the ester of fatty acid.
Such preparation can separate administration with estradiol administration, or administration simultaneously.
The compositions of the solution form that contains estradiol and progesterone is to be used for the treatment of the useful products with complete endometrial postmenopausal women, and such compositions is also useful contraception product.
Therefore, further, the solution of a kind of non-aqueous (or being non-aqueous substantially) is provided, the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, with the progesterone of 0.1 to 5% (w/v), the C of 10-30% (v/v) or 5-40% (v/v) 2-C 5the C of alcohol and 70-90% (v/v) or 60-95% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid, at one or more time points, by single or multiple administration, by the described solution of oral mucosa administration doses, the mankind women who is used for the treatment of the estradiol level with reduction, or for the manufacture for the treatment of, there is mankind women's the medicine of the estradiol level of reduction, described dosage contains 0.01-0.3mg estradiol, or acceptable hydrate or ester on its materia medica of equivalent, and contain 0.1-3mg progesterone.
Another aspect relates to the solution of a kind of non-aqueous (or being non-aqueous substantially), the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, and the progesterone of 0.1 to 5% (w/v), the C of 10-30% (v/v) 2-C 5the C of alcohol and 70-90% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid.
An embodiment relates to the solution of a kind of non-aqueous (or being non-aqueous substantially), the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, with the progesterone of 0.1 to 5% (w/v), the isopropyl myristate of the ethanol of 10-30% (v/v) and 70-90% (v/v).
The invention still further relates to and comprise or contain just like the estradiol solution describing in detail herein with as the product of the progesterone solution specially illustrating herein, as for simultaneously, separately or the combination prepared product using according to the order of sequence, be used for the treatment of the women of the estradiol level with reduction.
Solution of the present invention is remarkable in the buccal absorption that strengthens estradiol.The present invention is by complete anhydrous solution composition, it contains ethanol and isopropyl myristate (or isopropyl palmitate), and these components all contribute to buccal absorption efficiency, and total bioavailability of estradiol is good as oral mucosa Aerodiol surprisingly tMthe twice of administration.
By following non-limiting example, the present invention is described.
Embodiment
embodiment 1: estradiol spraying 0.3%
Estradiol 30mg
Ethanol 2ml
Isopropyl myristate 8ml
100μl＝300μg
50μl＝150μg
25μl＝75μg
embodiment 2: estradiol spraying 0.2%
Estradiol 20mg
Ethanol 1.5ml
Isopropyl myristate 8.5ml
100μl＝200μg
50μl＝100μg
25μl＝50μg
embodiment 3: estradiol spraying 0.1%
Estradiol 10mg
Ethanol 1ml
Isopropyl palmitate 9ml
100μl＝100μg
50μl＝50μg
25μl＝25μg
embodiment 4:estradiol spraying 0.05%
Estradiol 5mg
Ethanol 2ml
Isopropyl palmitate 8ml
100μl＝50μg
50μl＝25μg
20μl＝10μg
embodiment 5: estradiol spraying 0.4%
Estradiol 40mg
Ethanol 1.5ml
Isopropyl myristate 8.5ml
100μl＝400μg
50μl＝200μg
25μl＝100μg
embodiment 6: estradiol level during administration solution of the present invention
The scope of normal estradiol level represents (272ng/l=272pg/ml=1nmol/l) with the estradiol of ng/l or pg/ml.
In the women of childbearing age, during the different piece of menstrual cycle, normal estradiol level scope is 100-500pg/ml.
At perimenopause, estradiol level, lower than 100pg/ml, at postmenopause, is down to 10-20pg/ml.Value scope lower than the normal estradiol level of 100pg/ml is relevant to upsurge, and can send the signal of menopause.
In the independent situation of postmenopausal women, carry out these experiments.Administration (spraying by the cheek described in administration embodiment 1 and 3) is 30 minutes (25-35 minute) after the estradiol of dosage several times, has measured the serum levels of estradiol.Result:
The raising of finding the estradiol serum levels of every 10 μ g estradiol dosage changes between 40-50pg/ml.For example, every 150 μ g estradiol dosage rises to about 700pg/ml.
By these levels with from the use nose Aerodiol of document tMthe level obtaining is compared, Aerodiol tMit is the aqueous solution of estradiol-cyclodextrin complexes.Nose spraying (each nostril once) as 2 150 μ g gives, after the estradiol of 300 μ g dosage, to use Aerodiol tMthe average peak serum levels (Cmax) obtaining is approximately 1400pg/ml, and spray after 150 μ g estradiol at single nose, this level is (Devissaguet etc., Eur.J.Drug Metabol.Pharmacokinetics1999 between 600-800pg/ml; 24:265-271).
The serum estradiol level obtaining after oral mucosa administration solution of the present invention is closely similar, shows estradiol content and the nasal administration products A erodiol of the oral mucosa spray absorber from oral cavity tMtime the estradiol content that absorbs in nose similar.
Yet, disclosed Aerodiol tMproduct feature disclose by oral mucosa approach take (nasal obstruction women in) Aerodiol tMtime, estradiol absorption and therefore Cmax and AUC are down to 50%.The women of nasal obstruction must take the Aerodiol of double content tMspraying.The good twice of estradiol that this means the solution of the present invention absorbing via oral mucosa approach, this is surprising result (table 1).
table 1: use the AUC of estradiol and the comparison of Cmax of similar dosage
In other embodiments, 4 postmenopausal womens have been accepted cheek spraying 2 * 25 μ l estradiol 0.2% (embodiment 2), represent the estradiol of 100 μ g dosage.The serum levels following (table 2) of the estradiol in 3 hours processes:
table 2
Conclusion:
Result shows that average estradiol level was kept above 100pg/ml over 3 hours; represent to use the spray bottle that contains solution of the present invention; the therapeutic regimen of the estradiol that comprises the 100 μ g dosage by oral mucosa administration is just being protected women to avoid upsurge to surpass 3 hours, upsurge and Horizontal correlation lower than 100pg/ml.If upsurge is relevant to the estradiol level lower than 50pg/ml, this protection is even longer.
In addition, give oral mucosa dosage 2-4 time of 100 μ g every day, while using the dosing interval of 3-4 hour, for the most of the time of that day, by protection women avoid to lower than 50 or the relevant upsurge of the estradiol level of 100pg/ml.
Result also provides evidence, and oral mucosa is administered twice, respectively does for oneself for three times or four times after the estradiol of 150 μ g, 100 μ g and 75 μ g, and the AUC of measurement (serum levels area under a curve) uses 300 μ g nose estradiol (Aerodiol with nose estradiol tM) after total AUC roughly similar.This shows the nose Aerodiol that the oral mucosa estradiol spraying described in the present invention and calendar year 2001 have been ratified by administrative organization in Europe tMbioequivalent.

Claims (20)

1. non-aqueous (or substantially non-aqueous) solution, the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, the C of 5-30% (v/v) 2-C 5the C of alcohol and 70-95% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid, at one or more time points, by single or multiple administration, the mankind women who is used for the treatment of the estradiol level with reduction by the described solution of oral mucosa administration doses, described dosage contains 0.01-0.3mg estradiol, or acceptable hydrate or ester on its materia medica of equivalent.
2. solution according to claim 1, the estradiol solution that wherein said dosage comprises about 10-500 μ l.
3. solution according to claim 1 and 2, wherein 1-6 described dosage of administration every day.
4. according to the solution described in any one in claim 1-3, wherein with the interval of 1 to 4 hour, carry out off and on dosage described in administration.
5. according to the solution described in any one in claim 1-4, be used for the treatment of, prevent or alleviate the symptom being caused by not enough endogenous estrogen growing amount, as headache, feel sick, vasomotor symptoms (upsurge), the symptom of urogenital atrophy be, the risk of bone fracture of the reduction of bone mineral density, osteoporosis and raising or incidence rate.
6. non-aqueous (or substantially non-aqueous) solution, the estradiol that it contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, the C of 10-30% (v/v) 2-C 5the C of alcohol and 70-90% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid.
7. solution according to claim 6, wherein C 2-C 6alcohol and C 8-C 22the ester of fatty acid is isopropyl myristate, and C 2-C 5alcohol is ethanol.
8. according to the solution described in claim 6 or 7, wherein said solution contains 10-30% ethanol (v/v).
9. solution according to claim 8, the estradiol that it comprises 0.01-0.9% (w/v), the isopropyl myristate of the ethanol of 10-30% (v/v) and 70-90% (v/v).
10. according to the solution described in any one in claim 6-9, wherein C 2-C 5alcohol and C 2-C 6alcohol and C 8-C 22the volume ratio of the ester of fatty acid is 30:70,25:75,20:80,15:85 or 10-90 (v/v%).
11. according to the solution described in any one in claim 1-10, wherein by spraying, pass through drop or passing through fountain-pen dosimeter, the described solution of administration 10 μ l to 500 μ l volumes.
12. 1 kinds of treatments have women's the method for the estradiol level of reduction, described method is included in one or more time points, the solution oral mucosa of doses is delivered medicine to the mankind's female patients needing, the estradiol that described solution contains 0.01-0.9% (w/v), or acceptable hydrate or ester on its materia medica of equivalent, the C of 5-30% (v/v) 2-C 5the C of alcohol and 70-95% (v/v) 2-C 6alcohol and C 8-C 22the ester of fatty acid; Wherein by single or multiple administration, give described dosage, and described dosage comprises 0.01-0.3mg estradiol, or acceptable hydrate or ester on its materia medica of equivalent.
13. methods according to claim 12, wherein select the dosage of described solution and the number of times of administration, make estradiol serum levels that patient obtains in the scope of 10-500pg/ml.
14. methods according to claim 12, wherein select the dosage of described solution and the number of times of administration, make estradiol serum levels that patient obtains higher than 20pg/ml over 3 hours.
15. methods according to claim 12, wherein for every 0.05mg estradiol of administration, have obtained the controlled raising of the patient's estradiol serum levels between about 150-300pg/ml.
16. methods according to claim 12, wherein for every 0.025mg estradiol of administration, have obtained the controlled raising of the patient's estradiol serum levels between about 75-150pg/ml.
17. methods according to claim 12, wherein the estradiol solution of the every dose of about 10-500 μ of administration l content.
18. methods according to claim 12, wherein administration every day 1-6 agent.
19. methods according to claim 12, wherein at dosage described in the time period discontinuous ground administration of 1 to 4 hour scope.
20. methods according to claim 1, wherein in female patients, the rising of estradiol level and control obtain following result: treat, prevent or alleviated the symptom being caused by not enough endogenous estrogen growing amount, as headache, feel sick, vasomotor symptoms (upsurge), the symptom of urogenital atrophy be, the risk of bone fracture of the reduction of bone mineral density, osteoporosis and raising or incidence rate.
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Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2885523T3 (en) 2011-11-23 2021-12-14 Therapeuticsmd Inc Natural combination hormone replacement formulations and therapies
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US20150196640A1 (en) 2012-06-18 2015-07-16 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US20130338122A1 (en) 2012-06-18 2013-12-19 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
AU2015264003A1 (en) 2014-05-22 2016-11-17 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
WO2017173071A1 (en) 2016-04-01 2017-10-05 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL8801670A (en) 1988-07-01 1990-02-01 Walter Adrianus Josephus Johan PHARMACEUTICAL PREPARATION.
US5073374A (en) 1988-11-30 1991-12-17 Schering Corporation Fast dissolving buccal tablet
JPH06321771A (en) 1992-07-31 1994-11-22 Tanabe Seiyaku Co Ltd Base for percutaneous administration
US5766620A (en) * 1995-10-23 1998-06-16 Theratech, Inc. Buccal delivery of glucagon-like insulinotropic peptides
US5955098A (en) 1996-04-12 1999-09-21 Flemington Pharmaceutical Corp. Buccal non polar spray or capsule
WO1997038662A2 (en) 1996-04-12 1997-10-23 Flemington Pharmaceutical Corporation Buccal polar spray or capsule
US20030077229A1 (en) * 1997-10-01 2003-04-24 Dugger Harry A. Buccal, polar and non-polar spray or capsule containing cardiovascular or renal drugs
AU2004285335B2 (en) * 2003-10-23 2011-02-10 Cipla Limited Transdermal pharmaceutical spray formulations comprising a VP/VA copolymer and a non-aqueous vehicle
JP2007511544A (en) 2003-11-19 2007-05-10 アクルックス・ディ・ディ・エス・プロプライエタリー・リミテッド Compositions and methods for prevention or treatment of amyloidosis
CA2646667C (en) * 2006-04-21 2014-03-11 Antares Pharma Ipl Ag Methods of treating hot flashes with formulations for transdermal or transmucosal application
EP1867321A3 (en) 2006-06-07 2008-11-19 Familplan Consulting Ltd. A pharmaceutical product adapted for oral transmucosal administration comprising a pharmaceutical agent
AR068408A1 (en) 2007-09-14 2009-11-18 Drugtech Corp SPRAYING OF TRANSDERMAL HORMONES
WO2009101021A2 (en) 2008-02-13 2009-08-20 Bayer Schering Pharma Aktiengesellschaft Estradiol-containing drug delivery system
DE102009007771B4 (en) 2009-02-05 2012-02-16 Bayer Schering Pharma Aktiengesellschaft Buccal administration system containing 17α-estradiol

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